UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA.

Safer without PUMA

Gastrointestinal toxicity is a major cause of side effects from chemotherapy and radiation, which can greatly decrease the quality of life and limit the dosing of cancer treatments. Tumor suppressor p53 plays a major role in chemotherapy-induced intestinal cell death, but inhibiting p53 is not safe because a loss of p53 would worsen cancer growth. Instead, Leibowitz et al. showed that one can block only the detrimental function of p53 by inhibiting its downstream effector, PUMA. A small-molecule inhibitor of PUMA protected intestinal cells in mice and in human colon organoids but did not protect cancer cells, suggesting that this could be a viable strategy for intestinal protection in cancer patients.

Abstract

The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type–specific outcomes via distinct effectors. We demonstrate that p53-dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of Puma, but not of p53, protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5+ stem cells by Puma KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact.